Liraglutide has the following sequence: H-His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys(N-ε-(N-α-Palmitoyl-L-γ-glutamyl))-Glu-Phe-Ile-Ala-Trp-Leu-Val-Arg-Gly-Arg-Gly-OH (SEQ ID No. 1). Liraglutide, developed by Novo Nordisk, Denmark, is a glucagon-like peptide-1 (GLP-1) receptor agonist, which has favorable hypoglycemic effect as a formulation for subcutaneous injection.
Liraglutide from Novo Nordisk is prepared primarily by biological methods, such as genetic engineering, etc. Such methods, however, are not suitable for large-scale production of liraglutide, due to its complex techniques and high cost. Solid-liquid phase synthesis of liraglutide has been described in U.S. Pat. Nos. 6,268,343B1 and 6,458,924B2, in which reverse-phase HPLC is required for the purification of the intermediate GLP-1(7-37)-OH, followed by reaction with Nα-alkanoyl-Glu(ONSu)-OtBu in liquid phase. In such process, the N-terminal of GLP-1(7-37)-OH is not protected and protective groups for the side chains are all removed, leading to generation of a great amount of impurities, difficulties in purification and complicated operation steps. The synthesis methods of liraglutide in the prior art have disadvantages, such as, complicated operation process requiring two purification steps, long synthesis cycle, large amount of waste liquid which is not environmentally friendly, a great amount of acetonitrile required, high cost and unsuitability in large-scale production.